The chemical control of breathing is determined in large part by the physiology of central chemoreceptors. The location of these chemoreceptors and their importance relative to the carotid body are poorly understood. Is the breathing response which is caused by these receptors due to changes in blood pH or to brain extracellular fluid (ecf) pH? Both views have experimental support. Importantly related to this problem is the fact that the physiological mechanisms involved in cerebrospinal fluid (CSF) acid-base regulation, which may be quite relevant to central chemoreception, are also poorly understood. This project focuses on understanding the mechanisms of CSF acidbase regulation in metabolic acidemia and using this knowledge to determine the location of the central chemoreceptors and their relative importance. The approach emphasizes the ionic changes which must occur in CSF during acid-base imbalance as CSF has no nonbicarbonate buffers and builds on a hypothesis for CSF acid-base regulation which states that CSF [HCO3] is 1) primarily determined by PCO2 related changes in the ionic composition of freshly formed CSF, and 2) an ionic exchange process at the blood-brain barrier (BBB). In unanesthetized cats, different metabolic acids will be infused. The PCO2 will be kept constant or allowed to decrease in order to control for and evaluate the PCO2 specific mechanisms of CSF acid-base regulation. The CSF response will be evaluated by simple time course measurements and partitioned into PCO2 specific bulk flow and BBB specific ionic exchange components by a ventriculo-cisternal perfusion technique. The ventilatory response will be evaluated in cats with prior removal of peripheral chemoreceptors. The anions of the different acids are chosen so that penetration into CSF is to different extents due to different blood-brain barrier permeabilities or transport processes. By the use of the same degree of metabolic acidemia with these different acids, the specificity of blood-brain barrier acid-base regulatory processes for HCO3 or for acid anions will be tested as will the ability of the central chemoreceptors to sense blood vs brian ecf pH changes. The knowledge gained will further the understanding of basic physiological processes involved in the central chemical control of breathing and in CSF acid-base regulation.